Safe and effective approaches for the treatment of cocaine addiction are needed to address the tremendous burden of substance abuse disorders. An expanded mechanistic appreciation of the molecular, neural, and behavioral bases of reward is needed to identify integral pharmacotherapeutic targets for addiction. Interestingly, over 400,000 Americans are active cocaine users but are not considered cocaine dependent. These individuals have an underlying resilient neurobiology which makes them resistant to the development of addiction to cocaine. Studying this neurobiology of resilience may provide insight into the molecular, neural, and behavioral basis of addiction and lead to novel pharmacotherapeutic targets for cocaine addiction. An innovative prospect in this regard is neuromedin U (NMU), a highly conserved neuropeptide which has been shown to inhibit intake of food, a natural reward. These effects of NMU may be due to actions in the ventral tegmental area (VTA), the origin of the mesoaccumbens system. Little is known about the involvement of NMU in mesoaccumbens circuit, although recent data demonstrate that NMU administration increases neuronal activity in a terminal area of this circuit, the nucleus accumbens. Preliminary data indicates that expression is increased in the VTA in response to acute or chronic cocaine, a response which shows high levels of individual differences, with some animals in the range of controls while others are fivefold higher than controls. Also, we found that peripheral injection o NMU can block behavioral sensitization to cocaine. The goal of the present proposal is to explore NMU signaling in the VTA as a key mechanism that underlies behavioral responses to cocaine. To this end, it will be determined if changes in expression of NMU in the VTA can predict the magnitude of behavioral responses to cocaine. In addition, we seek to demonstrate a role for NMU in the behavioral effects of cocaine via use of RNAi-mediated knockdown of NMU in the VTA followed by assessment of locomotor sensitization to cocaine. Overall, linking NMU signaling in the VTA with the behavioral effects of cocaine will promote the idea that NMU signaling underlies behavioral responses to drugs of abuse, and support its potential as a novel therapeutic target to treat addiction.